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首页> 外文期刊>Cell cycle >A novel effect of DNA methyltransferase and histone deacetylase inhibitors: NFkappaB inhibition in malignant myeloblasts.
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A novel effect of DNA methyltransferase and histone deacetylase inhibitors: NFkappaB inhibition in malignant myeloblasts.

机译：DNA甲基转移酶和组蛋白脱乙酰基酶抑制剂的新作用：在恶性成肌细胞中抑制NFkappaB。

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摘要

Malignant myeloblasts arising in high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are characterized by the constitutive activation of the anti-apoptotic transcription factor NFkappaB. We found that DNA methyltransferase (DNMT) inhibitors (such as azacytidine and 5-aza-2'-deoxycytidine) and histone deacetylase (HDAC) inhibitors (such as trichostatin and valproic acid) efficiently induced apoptosis in the P39 MDS/AML cell line, correlating with an inhibition of NFkappaB (which translocated from the nucleus to the cytoplasm). This effect was obtained rapidly, within a few hours, suggesting that it was not due to epigenetic reprogramming. Indeed, DNMT and HDAC inhibitors reduced the phosphorylation of the NFkappaB-activating kinase IKKalpha/beta, and this effect was also observed in enucleated cells. Finally, circulating myeloblasts from AML patients treated with the DNMT inhibitor 5-aza-2'-deoxycytidine manifested a rapid (2 hours post-treatment) inhibition of NFkappaB and IKKalpha/beta. Altogether, these results indicate that DNMT and HDAC inhibitors can inhibit the constitutive activation of NFkappaB in malignant myeloblasts in vitro and in vivo through a novel mechanism.
机译：高危骨髓增生异常综合症（MDS）和急性髓细胞性白血病（AML）中产生的恶性成纤维细胞的特征在于抗凋亡转录因子NFkappaB的组成型激活。我们发现DNA甲基转移酶（DNMT）抑制剂（例如氮杂胞苷和5-氮杂2'-脱氧胞苷）和组蛋白脱乙酰基酶（HDAC）抑制剂（例如曲古抑菌素和丙戊酸）可以有效诱导P39 MDS / AML细胞系凋亡。与NFkappaB（其从细胞核转移到细胞质）的抑制作用有关。在数小时内迅速获得了这种效果，表明它不是由于表观遗传重编程。实际上，DNMT和HDAC抑制剂减少了NFkappaB激活激酶IKKalpha / beta的磷酸化，并且在去核细胞中也观察到了这种作用。最后，使用DNMT抑制剂5-氮杂2'-脱氧胞苷治疗的AML患者的成环成纤维细胞表现出对NFkappaB和IKKalpha / beta的快速抑制作用（治疗后2小时）。总而言之，这些结果表明，DNMT和HDAC抑制剂可以通过新颖的机制在体外和体内抑制恶性成肌细胞中NFkappaB的组成型活化。

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